title: Impact of food and the proton pump inhibitor rabeprazole on the pharmacokinetics of GDC-0941 in healthy volunteers: bench to bedside investigation of pH-dependent solubility.
abstract: GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.
authors.affiliation: Small Molecule Clinical Pharmacology, ‡Small Molecule Pharmaceutical Sciences, §Drug Metabolism and Pharmacokinetics, ∥Clinical Project Management, and ⊥Early Clinical Development, Genentech Research and Early Development , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
authors.forename: Gena
authors.initials: G
authors.lastname: Dalziel
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.forename: Jackson D
authors.initials: JD
authors.lastname: Pellett
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Smelick
authors.forename: David A
authors.initials: DA
authors.lastname: West
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sutton
authors.forename: Jane
authors.initials: J
authors.lastname: Fridyland
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
authors.forename: Glenn
authors.initials: G
authors.lastname: Morrisson
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001682:Biological Availability; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000493:pharmacokinetics; D054328:Proton Pump Inhibitors / Q000009:adverse effects; D064750:Rabeprazole / Q000009:adverse effects; D012995:Solubility; D013449:Sulfonamides / Q000493:pharmacokinetics; D006801:Humans
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D007191:Indazoles; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D013449:Sulfonamides